Affinage

CSNK1A1

Casein kinase I isoform alpha · UniProt P48729

Length
337 aa
Mass
38.9 kDa
Annotated
2026-06-09
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CK1α (CSNK1A1) is a constitutively active serine/threonine kinase that functions as a hierarchical, priming-dependent regulator of protein stability and signalling across the Wnt/β-catenin, Hedgehog, p53, Hippo (YAP), circadian, and cell-death pathways (PMID:21331045, PMID:20048001, PMID:16326393, PMID:31932442). A recurring theme is that CK1α phosphorylation creates phosphodegrons that license SCF(β-TrCP)/Slimb- or other E3-mediated ubiquitination and degradation of its substrates: it primes/completes β-catenin destruction-complex turnover by phosphorylating β-catenin at Ser45 and APC repeat-3 in a multi-step cascade (PMID:17172446, PMID:17910481), phosphorylates YAP Ser381 to recruit SCF(β-TRCP) (PMID:20048001), phosphorylates Ci/Gli to direct SCF(Slimb) processing (PMID:16326393), and phosphorylates PER1/PER2 for clock-protein degradation (PMID:21179498, PMID:35810166). In vivo, CK1α acts as a tumour suppressor in the gut, where its loss triggers concurrent Wnt and p53 activation and, when combined with p53 loss, drives invasive carcinoma (PMID:21331045); it also restrains p53 through a stable MDM2–CK1α complex and direct phosphorylation of the p53 N-terminus (PMID:19759023, PMID:10606744, PMID:20041275). CK1α additionally executes apoptotic and necroptotic programs by activating p63 and by phosphorylating RIPK3 at Ser227 within the necrosome (PMID:29483652, PMID:31932442). Its catalytic output is autoregulated: C-terminal autophosphorylation inhibits activity, while autophosphorylation of a conserved αG-helix threonine remodels the substrate cleft to rewire substrate selectivity (PMID:19115251, PMID:35353987). Substrate and spatial specificity are imposed by scaffold/docking partners—axin, FAM83D at the mitotic spindle, FAM83F at the plasma membrane, and PER as a clock scaffold—that localize the kinase to defined complexes (PMID:17434749, PMID:31338967, PMID:33361109, PMID:35810166). Pharmacologically, IMiDs such as lenalidomide convert CK1α into a neosubstrate of the CRL4(CRBN) E3 ligase via a CRBN/lenalidomide-formed interface engaging the CK1α kinase N-lobe, and CK1α haploinsufficiency in del(5q) MDS underlies the therapeutic window of this degradation (PMID:26131937, PMID:26909574).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 Medium

    Established that CK1 phosphorylates the p53 N-terminal MDM2-binding domain in a priming-dependent manner, introducing CK1 as a regulator of the p53–MDM2 axis.

    Evidence In vitro kinase assay with recombinant CK1δ and p53, phospho-site mapping

    PMID:10606744

    Open questions at the time
    • Used CK1δ, not CK1α, in a peptide context
    • No mutagenesis confirming the functional consequence in cells
    • Did not address docking determinants on full-length p53
  2. 2004 High

    Showed CK1 controls NFAT1 nuclear import through SRR-1 phosphorylation and a docking-motif-dependent association, defining CK1 as a gatekeeper of NFAT subcellular localization.

    Evidence In vitro kinase assay, co-IP, docking-motif mutagenesis, nuclear localization imaging

    PMID:15121840

    Open questions at the time
    • CK1 isoform specificity not fully resolved
    • Mechanism of signal-induced complex dissociation upon activation not defined
  3. 2005 High

    Connected CK1α to mitotic regulation and to negative control of canonical Wnt output by phosphorylating FADD (spindle-pole localized) and LEF-1 to disrupt the LEF-1/β-catenin complex.

    Evidence In vitro kinase assays, co-IP, immunofluorescence, EMSA, luciferase reporter, splenocyte proliferation

    PMID:15747065 PMID:16061179

    Open questions at the time
    • How CK1α is recruited to spindle poles not yet defined
    • Physiological trigger of LEF-1 phosphorylation in vivo unclear
  4. 2006 Medium

    Defined the docking determinants for substrate recognition on β-catenin, showing the first armadillo repeat and α-catenin binding govern CK1 access to Ser45.

    Evidence In vitro kinase assay with deletion mutants, Km determination, competition assay

    PMID:17172446

    Open questions at the time
    • Reconstituted in vitro; in-complex regulation by axin/APC not addressed here
    • Single lab
  5. 2008 Medium

    Extended CK1α substrate scope to RNA-binding proteins and small GTPases, phosphorylating hnRNP-C, Star-PAP, and RhoB to modulate RNA binding, mRNA expression, and cytoskeletal dynamics.

    Evidence MS kinase identification, in vitro kinase assays, co-IP, RNA-binding and immunofluorescence functional readouts

    PMID:15687492 PMID:18305108 PMID:18590726

    Open questions at the time
    • Cellular contexts for each substrate not fully linked
    • PI-4,5-P2 sensitivity of CK1α within Star-PAP complex not structurally explained
  6. 2009 Medium

    Revealed both an autoregulatory brake (C-terminal autophosphorylation inhibits activity) and a p53-suppressive function via a stable MDM2–CK1α complex with defined S20 docking on full-length p53.

    Evidence MS autophosphorylation site mapping, phosphatase activation cycle, mutagenesis, reciprocal endogenous co-IP, RNAi, chemical inhibition

    PMID:19115251 PMID:19759023 PMID:20041275

    Open questions at the time
    • Structural basis of the MDM2–CK1α interface not resolved
    • How autophosphorylation status integrates with substrate selection in vivo unclear
  7. 2010 Medium

    Placed CK1 in the Hippo and circadian pathways by phosphorylating YAP Ser381 to create a β-TRCP phosphodegron and PER1 to drive its degradation, generalizing the phosphodegron mechanism.

    Evidence In vitro kinase cascade reconstitution, phospho-antibodies, ubiquitination assay; affinity-MS, siRNA, circadian reporter assays

    PMID:20048001 PMID:21179498

    Open questions at the time
    • Relative contributions of CK1α vs CK1δ/ε to YAP turnover not isolated
    • Clock kinase network redundancy complicates CK1α-specific assignment
  8. 2011 High

    Demonstrated in vivo that CK1α is a destruction-complex component and tumour suppressor whose ablation co-activates Wnt and p53, and detailed its dual roles in Hedgehog (Smoothened activation) and Wnt receptor signalling.

    Evidence Conditional knockout mouse epistasis; in vitro kinase, mutagenesis, immunofluorescence, Hh/Wnt reporter and co-IP epistasis

    PMID:21331045 PMID:21606194 PMID:21695114

    Open questions at the time
    • Context that switches CK1α between Smoothened activation and β-catenin destruction not defined
    • Mechanism coupling CK1α loss to p53 activation in gut left open
  9. 2014 High

    Positioned CK1α upstream of p53 in leukemia survival and refined Hedgehog control, showing CK1α knockdown induces p53-dependent myeloid differentiation and CK1 sustains Ci/Gli activator isoforms.

    Evidence In vivo pooled shRNA screen, p53-null rescue epistasis, expression profiling; in vitro kinase, mutagenesis, Drosophila and mammalian Hh assays

    PMID:24616378 PMID:25512501

    Open questions at the time
    • Direct CK1α substrate linking it to Rps6/p53 axis in AML not identified
    • Switch between Ci/Gli degradation and stabilization not mechanistically reconciled
  10. 2015 High

    Defined the therapeutically pivotal IMiD mechanism: lenalidomide converts CK1α into a CRL4(CRBN) neosubstrate, and del(5q) CK1α haploinsufficiency underlies the MDS therapeutic window; also linked CK1α–FADD to oncogenic KRAS-driven mitosis.

    Evidence Ubiquitination assays, IP, mouse-human CRBN swap rescue, MS; conditional KO mouse, MS, in vivo imaging

    PMID:25628462 PMID:26131937

    Open questions at the time
    • Why CK1α dosage sensitivity is unique to del(5q) not fully explained at the time
    • Endogenous (IMiD-independent) regulators of CK1α turnover unknown
  11. 2016 High

    Provided the structural basis of IMiD-dependent neosubstrate recognition, showing CRBN and lenalidomide jointly form the binding surface for a CK1α N-lobe β-hairpin loop.

    Evidence 2.45 Å X-ray crystallography of DDB1-CRBN–lenalidomide–CK1α, binding assays, mutagenesis

    PMID:26909574

    Open questions at the time
    • Does not address selectivity among CK1 isoforms for degradation
    • Native CK1α regulation independent of CRBN not addressed
  12. 2017 High

    Expanded CK1α into epithelial/progenitor biology and oncogenic RAS signalling: it phosphorylates PRMT1 to maintain epidermal progenitors, FOXO4 to drive its degradation, and its loss stabilizes both β-catenin and p53 to drive p53/KitL-dependent pigmentation.

    Evidence MS interactomes, co-IP, in vitro kinase, conditional/human mosaic knockouts; double KO mice with pharmacological rescue; CK1α activator xenografts

    PMID:28655862 PMID:28878021 PMID:28943242 PMID:28945225

    Open questions at the time
    • Tissue-specific determinants of CK1α substrate choice not unified
    • Whether CK1α activators are broadly tractable therapeutically remains untested beyond CRC models
  13. 2018 High

    Identified CK1α as an executioner kinase for cell-fate decisions, activating p63 in oocyte DNA-damage QC, stabilizing PTEN to promote autophagy/tumour suppression, and cooperating with DBT in clock PER localization.

    Evidence Biochemical/structural p63 assays with in vivo rescue; co-IP, ubiquitination, xenografts; Drosophila genetics and fractionation

    PMID:29483652 PMID:29593330 PMID:30373768

    Open questions at the time
    • How CK1α is activated specifically upon DNA damage in oocytes unclear
    • CK1α–PTEN versus CK1α–p53 tumour-suppressive arms not integrated
  14. 2019 High

    Established scaffold-directed spatial control of CK1α by FAM83D, which recruits the kinase to the mitotic spindle to ensure correct spindle positioning and mitotic timing.

    Evidence CRISPR knockin of CK1α-binding-deficient FAM83D, live-cell imaging, knockout, artificial re-delivery rescue

    PMID:31338967

    Open questions at the time
    • Spindle-localized CK1α substrates not enumerated
    • Relationship to FADD-spindle phosphorylation not connected
  15. 2020 High

    Defined CK1α as a necrosome component phosphorylating RIPK3 Ser227 to license necroptosis, and identified additional substrate (CBX4) and localization controls (FAM83F farnesylation; RNF43-mediated membrane trapping in cancer).

    Evidence Tandem IP, in vitro kinase, RIPK3 recognition-motif rescue, necroptosis assays; CBX4 phospho/ubiquitination assays; CRISPR knockin and PLA

    PMID:31932442 PMID:32111827 PMID:32965059 PMID:33361109

    Open questions at the time
    • Isoform redundancy (α/δ/ε) in necrosome not dissected
    • How membrane-trapped CK1α alters its destruction-complex function quantitatively unclear
  16. 2022 High

    Revealed a second, conformational layer of autoregulation—αG-helix threonine autophosphorylation remodels the substrate cleft to rewire substrate selectivity—and showed PER itself scaffolds CK1 to control clock phosphorylation in vivo.

    Evidence Crystal structure, MD simulations, kinase assays, phosphoproteomics; CRISPR knock-in mice with locomotor and biochemical readouts

    PMID:35353987 PMID:35810166

    Open questions at the time
    • Physiological signals controlling αG autophosphorylation in mammalian cells unknown
    • How conformational rewiring intersects with scaffold-based targeting not addressed
  17. 2023 High

    Provided structural mechanism for substrate-driven product inhibition of CK1, with the phosphorylated PER2 FASP region docking near the active site to inhibit the kinase and tune circadian period.

    Evidence Co-crystal structure of pFASP–CK1δ, MD simulations, mutagenesis, circadian period assays in human cells

    PMID:37207626

    Open questions at the time
    • Studied with CK1δ; generality to CK1α not directly shown
    • Whether other substrates exert analogous product inhibition unknown
  18. 2024 Medium

    Advanced CK1α as a tractable degradation target with a selective CRBN-based degrader (SJ3149) whose antiproliferative activity tracks with p53 (Nutlin-3a) sensitivity, reinforcing the CK1α–p53 therapeutic axis.

    Evidence Structure-guided medicinal chemistry, co-crystal with CK1α+CRBN+DDB1, proteomics, PRISM screen, viability panel

    PMID:38228616

    Open questions at the time
    • p53 link inferred from correlation rather than direct mechanism
    • On-target versus off-target degradation contributions to phenotype not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CK1α's constitutive activity is selectively channeled to opposing outcomes (e.g., β-catenin destruction vs Smoothened activation; p53 suppression vs activation) through the combined logic of scaffold-based localization, docking-site recognition, and autophosphorylation-driven conformational rewiring remains unresolved.
  • No unified model integrating scaffold targeting, substrate docking, and αG/C-terminal autophosphorylation states
  • Endogenous signals controlling CK1α abundance and activity in each pathway incompletely defined
  • Isoform-specific (α vs δ/ε) contributions to many substrates unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005815 microtubule organizing center 3 GO:0005886 plasma membrane 3 GO:0005730 nucleolus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 5 R-HSA-9909396 Circadian clock 4 R-HSA-1640170 Cell Cycle 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1
Partners
AXIN1CRBNFAM83DFAM83FMDM2PER2PTENRIPK3
Complex memberships
MDM2-CK1α complexStar-PAP complexnecrosomeβ-catenin destruction complex

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Lenalidomide induces ubiquitination and degradation of CK1α by the CRL4(CRBN) E3 ubiquitin ligase (CUL4-RBX1-DDB1-CRBN); haploinsufficiency of CK1α in del(5q) MDS sensitizes cells to this degradation, providing the mechanistic basis for lenalidomide's therapeutic window in del(5q) MDS. Ubiquitination assays, immunoprecipitation, mouse-human CRBN single amino acid swap rescue experiment, mass spectrometry Nature High 26131937
2016 Crystal structure (2.45 Å) of DDB1-CRBN bound to lenalidomide and CK1α shows that CRBN and lenalidomide jointly provide the binding interface for a CK1α β-hairpin-loop in the kinase N-lobe; CK1α binding to CRL4(CRBN) is strictly IMiD-dependent. X-ray crystallography, binding assays, mutagenesis Nature High 26909574
2011 CKIα is a component of the β-catenin destruction complex; conditional ablation of Csnk1a1 in mouse gut triggers massive Wnt/β-catenin activation and concurrent p53 activation; combined loss of CKIα and p53 (or p21) drives invasive carcinoma, establishing CKIα as a tumour suppressor downstream of p53. Conditional knockout (Cre-lox) mouse model, histology, gene expression profiling, epistasis analysis Nature High 21331045
2010 CK1α phosphorylates YAP at Ser381 (after Lats primes it), creating a phosphodegron that recruits SCF(β-TRCP) E3 ubiquitin ligase leading to YAP ubiquitination and degradation; CK1δ/ε are identified as the relevant isoforms for this step. In vitro kinase assay, phospho-specific antibodies, co-immunoprecipitation, ubiquitination assay, mutagenesis Genes & Development High 20048001
2010 CK1α acts as a clock regulatory kinase that phosphorylates PER1 to stimulate its degradation; siRNA knockdown of CKIα lengthens circadian period; combinatorial knockdown of CKIδ, CKIα and ERK2 dramatically lengthens period, revealing a multi-kinase network for clock robustness. Affinity chromatography/mass spectrometry target identification, siRNA knockdown, circadian reporter assays, chemical inhibition PLoS Biology Medium 21179498
2011 CK1α phosphorylates the carboxyl-terminal tail of mammalian Smoothened (mSmo) at multiple sites to induce its active conformation and promote ciliary accumulation; Hh signaling recruits CK1α to initiate mSmo phosphorylation, and phosphorylation further increases CK1α/GRK2 binding, forming a positive feedback loop. In vitro kinase assay, phosphorylation-site mutagenesis, co-immunoprecipitation, immunofluorescence, cell-based Hh signaling assays PLoS Biology High 21695114
2005 CKIα phosphorylates FADD at Ser194 both in vitro and in vivo; FADD-CKIα association regulates subcellular localization of FADD, with phosphorylated FADD co-localizing with CKIα at spindle poles in metaphase; CKIα inhibition prevents Taxol-induced mitotic arrest and blocks mitogen-induced proliferation. In vitro kinase assay, co-immunoprecipitation, immunofluorescence, pharmacological inhibition, splenocyte proliferation assay Molecular Cell High 16061179
2015 CK1α phosphorylates FADD downstream of oncogenic KRAS, promoting mitotic entry; deletion of CK1α in KRAS-mutant mice abrogates FADD phosphorylation and suppresses lung cancer development; phosphorylated FADD interacts with PLK1, AURKA, and BUB1 in a CK1α-dependent manner during G2/M. Conditional knockout mouse model, mass spectrometry, immunohistochemistry, in vivo imaging, kinase inhibitor treatment Science Signaling High 25628462
2009 CK1α forms a stable complex with MDM2 in undamaged cells; depletion or inhibition of CK1α stabilizes p53 and destabilizes E2F-1, indicating CK1α is a negative regulator of p53 and positive regulator of E2F-1 through the MDM2-CK1α complex. siRNA knockdown, pharmacological inhibition (D4476), co-immunoprecipitation of endogenous proteins, western blot Journal of Biological Chemistry Medium 19759023
2014 Csnk1a1 knockdown in AML cells results in decreased Rps6 phosphorylation and increased p53 activity leading to myeloid differentiation; p53-null leukemias are insensitive to Csnk1a1 knockdown, placing CK1α upstream of p53 in a leukemia-survival pathway. shRNA knockdown, in vivo pooled shRNA screen, gene expression profiling, pharmacological inhibition (D4476), flow cytometry Journal of Experimental Medicine High 24616378
2008 CKIα is associated with the nuclear poly(A) polymerase Star-PAP and directly phosphorylates it; CKIα and PIPKIα are both required for expression of a subset of Star-PAP target mRNAs; CKIα activity is PI-4,5-P2-sensitive within the Star-PAP complex. Mass spectrometry, co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, qRT-PCR Journal of Biological Chemistry Medium 18305108
1999 CK1 phosphorylates p53 at Thr18 in vitro; this phosphorylation requires prior phosphorylation of Ser15, establishing a phosphorylation-priming hierarchy at the MDM2-binding domain of p53. In vitro kinase assay with recombinant CK1δ and p53, phospho-site mapping FEBS Letters Medium 10606744
2009 CK1α and CK1δ directly phosphorylate p53 preferentially at S20 (not S6); affinity for full-length p53 is ~1000-fold higher than for the N-terminal peptide, implicating a remote docking site mapped to the K221RQK224 loop; CK1γ1 does not phosphorylate p53. In vitro kinase assay with recombinant isoforms, Km determination, mutagenesis of docking loop Cellular and Molecular Life Sciences Medium 20041275
2008 PML enhances CK1-mediated phosphorylation of p53 at Thr18 in response to DNA damage; CK1 interacts with endogenous p53 and PML and this interaction is enhanced by genotoxic stress; PML facilitates Thr18 phosphorylation by recruiting p53 and CK1 into PML nuclear bodies, protecting p53 from MDM2-mediated degradation. Co-immunoprecipitation, immunofluorescence, phospho-specific antibodies, CK1 inhibitor treatment Oncogene Medium 18246126
2004 CK1 phosphorylates NFAT1 specifically at the SRR-1 motif (required for nuclear import); CK1 exists with NFAT1 in a high-molecular-weight complex in resting T cells but dissociates upon activation; a conserved docking motif in NFAT proteins is required for CK1 interaction, and its mutation causes constitutive nuclear localization of NFAT1. In vitro kinase assay, co-immunoprecipitation, mutagenesis, nuclear localization imaging Molecular and Cellular Biology High 15121840
2018 CK1 is the executioner kinase for p63 activation in oocyte DNA-damage quality control; both CHK2 (priming) and CK1 (execution) phosphorylations are required to induce p63's active tetrameric conformation; CK1 inhibition rescues primary oocytes from chemotherapy-induced apoptosis. Biochemical phosphorylation assays, structural analysis of p63 conformational changes, mouse primordial follicle experiments, CK1 inhibitor rescue Nature Structural & Molecular Biology High 29483652
2020 CK1α, CK1δ, and CK1ε are necrosome components that directly phosphorylate RIPK3 at Ser227 to activate necroptosis; this interaction depends on RIPK3 kinase activity; a RIPK3 CK1-recognition-motif mutant fails to be phosphorylated at S227, does not bind MLKL, and cannot activate necroptosis. Tandem immunoprecipitation, in vitro kinase assay, CK1 loss-of-function, RIPK3 recognition-motif mutagenesis, necroptosis assay PNAS High 31932442
2017 CSNK1a1 directly binds and phosphorylates PRMT1 to control its genomic targeting; loss of CSNK1a1 in epidermal progenitors (mouse and human) abolishes progenitor self-renewal and leads to premature differentiation through derepression of GRHL3. Mass spectrometry (PRMT1 interactome), co-immunoprecipitation, in vitro kinase assay, conditional mouse knockout, human mosaic epidermis in vivo regeneration Developmental Cell High 28943242
2018 CK1α suppresses NSCLC tumour growth by binding the C-terminal tail of PTEN and enhancing PTEN stability and activity by competitively antagonizing NEDD4-1-induced polyubiquitination and abrogating PTEN phosphorylation, thereby inhibiting AKT and activating FOXO3a-induced Atg7 transcription and autophagy. Co-immunoprecipitation, ubiquitination assay, in vitro binding assay, CK1α knockdown/overexpression, xenograft models Nature Cell Biology High 29593330
2020 CK1α phosphorylates CBX4 at T437, which facilitates CBX4 ubiquitination at K178 and K280 and subsequent CHIP-mediated degradation; TNFα reduces CK1α-mediated CBX4 phosphorylation; CK1α suppresses osteosarcoma cell migration and invasion through CBX4 inhibition. In vitro kinase assay, co-immunoprecipitation, ubiquitination assay, phospho-site mutagenesis, cell migration/invasion assays Nature Communications High 32111827
2013 CK1α phosphorylates RAPGEF2 in response to pro-motility factors, together with IKKβ, leading to proteasomal degradation via SCF(βTrCP); failure to degrade RAPGEF2 sustains Rap1 activity and inhibits HGF-induced cell migration. Phosphorylation assays, co-immunoprecipitation, degradation-resistant mutant expression, cell migration assays, xenograft metastasis model Developmental Cell Medium 24290981
2011 In the canonical Wnt pathway, CK1α associates with the LRP5/6/p120-catenin complex after Wnt3a stimulation in a CK1ε-dependent manner and within a complex with axin; CK1α participates in the release of p120-catenin from the LRP5/6 complex to activate downstream signalling. Co-immunoprecipitation, siRNA knockdown, Wnt reporter assays, sequential epistasis analysis Molecular and Cellular Biology Medium 21606194
2005 CK1 phosphorylates Ci (Drosophila Gli) at three PKA/GSK3-primed serine clusters, creating Slimb/β-TRCP binding sites that cooperatively recruit SCF(Slimb) ubiquitin ligase for Ci proteolytic processing; CKIα and DBT/CKIε act in conjunction for this step. In vitro kinase assay, mutagenesis of phosphorylation clusters, Slimb binding assay, Drosophila in vivo epistasis Developmental Cell High 16326393
2014 CK1 phosphorylates Ci/Gli activator isoforms at multiple Ser/Thr-rich degrons downstream of Costal2 and Sufu to inhibit HIB (Cullin3 E3 ligase substrate receptor)-mediated Ci(A) degradation, sustaining Hh pathway activity; Gli(A) is similarly regulated in vertebrates. In vitro kinase assay, mutagenesis, co-immunoprecipitation, Drosophila genetics, mammalian cell Hh reporter assays PNAS High 25512501
2006 CK1 phosphorylates β-catenin at Ser45; the first armadillo repeat of β-catenin is required for high-affinity CK1 recognition (removing it raises Km ~50-fold); α-catenin binding to β-catenin's N-terminal region prevents CK1-mediated Ser45 phosphorylation. In vitro kinase assay with deletion mutants, Km determination, competition assay PNAS Medium 17172446
2007 CK1 initiates phosphorylation of APC repeat-3 (R3) at S1510 and S1505 via non-canonical determinants; phospho-S1505 primes GSK3 phosphorylation of S1501; phospho-S1501 in turn triggers hierarchical CK1 phosphorylation of S1504 and S1507, completing a six-step cascade required for β-catenin degradation. In vitro kinase assay with variably phosphorylated peptides, Edman degradation phospho-site mapping Biochemistry Medium 17910481
2005 CK1 directly phosphorylates LEF-1 and disrupts the LEF-1/β-catenin complex (without impairing LEF-1/DNA binding); this requires co-phosphorylation of β-catenin; CK1-dependent phosphorylation inhibits LEF-1/β-catenin transcriptional activity, establishing CK1 as a second-level negative regulator of canonical Wnt signalling. In vitro kinase assay, GST pulldown, electrophoretic mobility shift assay, luciferase reporter assay Cellular and Molecular Life Sciences Medium 15747065
2005 CK1α phosphorylates hnRNP-C at Ser240 and Ser225-228 in response to physiological H2O2; phosphorylation at CK1α sites causes 14–500-fold decrease in hnRNP-C RNA-binding affinity, as shown by phosphomimetic mutations. Kinase purification and identification by tandem MS, in vitro kinase assay, co-immunoprecipitation, fluorescence RNA binding assay with phosphomimetic mutants Journal of Biological Chemistry High 15687492
2019 FAM83D recruits CK1α to the mitotic spindle; cells lacking FAM83D or carrying CK1α-binding-deficient FAM83DF283A/F283A knockin mutations display spindle positioning defects and prolonged mitosis; artificial re-delivery of CK1α to the spindle rescues these defects. CRISPR/Cas9 knockin, live-cell imaging, immunofluorescence, FAM83D knockout, spindle positioning assay EMBO Reports High 31338967
2020 Truncating RNF43 cancer mutations trap CK1 at the plasma membrane by disrupting a ubiquitin-independent suppressor function of the RNF43 cytosolic tail, thereby preventing β-catenin turnover and driving ligand-independent Wnt target gene transcription. Gene editing of human colon stem cells, co-immunoprecipitation, luciferase reporter assay, proximity ligation assay EMBO Journal Medium 32965059
2009 CK1α autophosphorylates its own C-terminal residues (last four Ser/Thr); this autophosphorylation inhibits catalytic activity; lambda phosphatase treatment activates CK1α by 80–100%, and re-autophosphorylation re-inhibits it, establishing autophosphorylation as a regulatory mechanism. Mass spectrometry of autophosphorylation sites, site-directed mutagenesis to Ala, lambda phosphatase treatment, in vitro kinase assay Journal of Cellular Biochemistry High 19115251
2007 CK1 (alpha, delta, epsilon isoforms) binds axin and can be purified by affinity chromatography on an immobilised axin fragment (residues 495–684); the purified enzymes retain high kinase activity, confirming a direct physical CK1α-axin interaction. Affinity chromatography, kinase activity assay Protein Expression and Purification Medium 17434749
2017 Oncogenic RAS elevates CK1α activity to phosphorylate FOXO4 at Ser265/268, triggering its proteasomal degradation; this is partially primed by AKT effectors of RAS signalling; dual inhibition of CK1α and the proteasome synergistically inhibits RAS-mutant cancer cell growth. In vitro kinase assay, phospho-site mutagenesis, CK1α inhibition, FOXO4 stability assays, cell viability assays Oncogene Medium 28945225
2020 FAM83F is farnesylated and interacts with CK1α at the plasma membrane; this interaction is essential for FAM83F-mediated Wnt pathway activation; a farnesyl-deficient FAM83F knockin redirects the FAM83F-CK1α complex away from the plasma membrane and attenuates Wnt signalling. Co-immunoprecipitation, CRISPR knockin of farnesyl-deficient mutant, Wnt reporter assay, Xenopus axis duplication assay Life Science Alliance Medium 33361109
2017 Decreased CK1α abundance in WNT-driven colorectal tumours (relative to normal tissue) enhances cellular sensitivity to CK1α activators; the small-molecule CK1α activator SSTC3 inhibits CRC xenograft growth; knockdown of CK1α increases sensitivity to SSTC3. Xenograft mouse models, CK1α knockdown, CK1α activator SSTC3 treatment, patient-derived xenograft Science Signaling Medium 28655862
2008 CK1 phosphorylates RhoB specifically at Ser185 in vitro and in cells; phosphorylation by CK1 inhibits RhoB, and CK1 inhibition activates RhoB-dependent actin stress fiber formation and EGF receptor stabilization; RhoA and RhoC are not phosphorylated by CK1. In vitro kinase assay, mass spectrometry phospho-site mapping, site-directed mutagenesis, CK1 inhibitors, immunofluorescence Experimental Cell Research Medium 18590726
2007 CK1 phosphorylates PKD2 at Ser244 in response to CCK2R activation; this phosphorylation blocks nuclear export of active PKD2 by preventing Crm-1 interaction, and is prerequisite for efficient phosphorylation of the nuclear PKD2 substrate HDAC7. In vitro kinase assay, co-immunoprecipitation, subcellular fractionation, nuclear export inhibition, mutagenesis EMBO Journal Medium 17962809
2002 The 'L' insert (exon L, 28 aa in catalytic domain) of CK1αL acts as a nuclear localization signal; CK1αL concentrates in the nucleus while CK1α is predominantly cytoplasmic; the L insert increases Km for ATP ~2-fold, decreases CKI-7 sensitivity, and accelerates protein turnover (half-life 100 min vs. 400 min for CK1α). Splice variant expression in Cos-7 cells, immunofluorescence, in vitro kinase assay, protein stability assay Journal of Cellular Biochemistry Medium 12210746
2022 Autophosphorylation of a conserved threonine (T220 equivalent) in the αG helix of CK1 alters the conformation of the substrate binding cleft, decreasing activity toward most substrates while increasing it toward specific high-affinity substrates; disrupting T220 autophosphorylation rewires CK1 signalling in S. pombe (confirmed by quantitative phosphoproteomics). Crystal structure of autophosphorylated CK1, molecular dynamics simulation, in vitro kinase assay, mutagenesis, quantitative phosphoproteomics Molecular Cell High 35353987
2013 CK1 transmits the signal to stall cytokinesis in a mitotic checkpoint by phosphopriming the SPB scaffold Sid4 for Dma1-mediated ubiquitination; CK1 accumulates at spindle pole bodies during mitotic arrest and stably associates with SPB components including Sid4. Yeast genetics, co-immunoprecipitation, kinase assay, SPB localization by fluorescence microscopy Current Biology Medium 24055157
2022 Mutation of PER2 residues essential for CK1 interaction abolishes PER phosphorylation and CLOCK hyperphosphorylation in cells and mice, resulting in PER stabilization and arrhythmic PER abundance; mice show robust short-period locomotor rhythms despite low-amplitude molecular rhythms, demonstrating PER acts as CK1 scaffold. Site-directed mutagenesis, CRISPR knock-in mice, circadian locomotor analysis, western blot for phosphorylation Nature Communications High 35810166
2023 The phosphorylated FASP region of PER2 directly docks into conserved anion-binding sites near the CK1δ active site to inhibit CK1 activity (product inhibition); crystal structures with molecular dynamics simulations reveal the pFASP-CK1δ interface; limiting FASP phosphorylation reduces product inhibition, decreasing PER2 stability and shortening circadian period. Co-crystal structure of pFASP-CK1δ, molecular dynamics simulations, site-directed mutagenesis, circadian period assay in human cells Molecular Cell High 37207626
2018 CK1α collaborates with DBT/CK1δ in the Drosophila clock: CK1α promotes PER nuclear localization by antagonizing DBT-dependent inhibition of nuclear translocation; once in the nucleus, CK1α enhances DBT-dependent PER phosphorylation and degradation. Drosophila genetics (knockdown/overexpression), locomotor rhythm analysis, nuclear/cytoplasmic fractionation, phosphorylation assays Journal of Neuroscience Medium 30373768
2024 SJ3149, a selective CK1α degrader developed through structure-guided SAR around CRBN ligands, shows broad antiproliferative activity correlated with MDM2 inhibitor Nutlin-3a response across 115 cancer cell lines; co-crystal structure of SJ3149 with CK1α+CRBN+DDB1 explains improved degradation properties. Structure-guided medicinal chemistry, co-crystal structure, proteomics, PRISM screen, cell viability panel Nature Communications Medium 38228616
2017 CK1α ablation in keratinocytes stabilises both β-catenin and p53; epidermal hyperpigmentation following CK1α loss requires p53-dependent upregulation of KitL (Kit ligand); co-ablation of CK1α and p53 fails to induce hyperpigmentation, and KitL/Kit pathway inhibition abrogates it. Conditional knockout mice (K14-Cre-ERT2), double knockout (CK1α/p53), transcriptome analysis, antibody/inhibitor rescue experiments PNAS High 28878021
2013 Reduced Csnk1a1 abundance downstream of DNA damage activates Wnt/β-catenin signalling in mouse embryonic stem cells in a p53-independent manner, limiting DNA-damage-induced apoptosis; this places CK1α as an inhibitor of β-catenin whose loss links DNA damage to Wnt activation. RNAi screen, transcriptomics, phosphoproteomics, gene deletion (p53 KO), Wnt reporter assay Science Signaling Medium 23354688

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes & development 1230 20048001
2015 Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 708 26131937
2016 Structural basis of lenalidomide-induced CK1α degradation by the CRL4(CRBN) ubiquitin ligase. Nature 481 26909574
2014 The CK1 Family: Contribution to Cellular Stress Response and Its Role in Carcinogenesis. Frontiers in oncology 231 24904820
2004 D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO reports 230 14710188
2010 Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proceedings of the National Academy of Sciences of the United States of America 210 20696890
2010 High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKIα as a clock regulatory kinase. PLoS biology 202 21179498
2011 Sonic Hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened. PLoS biology 180 21695114
2011 CKIα ablation highlights a critical role for p53 in invasiveness control. Nature 162 21331045
2007 Wnt-5a induces Dishevelled phosphorylation and dopaminergic differentiation via a CK1-dependent mechanism. Journal of cell science 152 17244647
2004 A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1. Molecular and cellular biology 151 15121840
2018 Oocyte DNA damage quality control requires consecutive interplay of CHK2 and CK1 to activate p63. Nature structural & molecular biology 133 29483652
2005 Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities. Molecular cell 129 16061179
2020 Targeting the CK1α/CBX4 axis for metastasis in osteosarcoma. Nature communications 126 32111827
2010 Protein kinases CK1 and CK2 as new targets for neurodegenerative diseases. Medicinal research reviews 123 20577972
2018 CK1α suppresses lung tumour growth by stabilizing PTEN and inducing autophagy. Nature cell biology 120 29593330
2005 Phosphorylation by double-time/CKIepsilon and CKIalpha targets cubitus interruptus for Slimb/beta-TRCP-mediated proteolytic processing. Developmental cell 118 16326393
1999 Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. FEBS letters 118 10606744
2012 Protein kinase CK1α regulates erythrocyte survival. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 113 22415086
2005 The role of the casein kinase 1 (CK1) family in different signaling pathways linked to cancer development. Onkologie 102 16186692
2014 Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis. Journal of medicinal chemistry 92 24592867
2008 Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo. Gut 89 18203806
2009 CK1alpha plays a central role in mediating MDM2 control of p53 and E2F-1 protein stability. The Journal of biological chemistry 88 19759023
2014 Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. The Journal of experimental medicine 85 24616378
2011 Coordinated action of CK1 isoforms in canonical Wnt signaling. Molecular and cellular biology 74 21606194
2010 Role of CK1 in GSK3beta-mediated phosphorylation and degradation of snail. Oncogene 74 20305697
2001 Catalytic activity of protein kinase CK1 delta (casein kinase 1delta) is essential for its normal subcellular localization. Experimental cell research 67 11161704
2020 Functions and regulation of the serine/threonine protein kinase CK1 family: moving beyond promiscuity. The Biochemical journal 66 33306089
2019 Structure, regulation, and (patho-)physiological functions of the stress-induced protein kinase CK1 delta (CSNK1D). Gene 64 31376410
2013 CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells. Oncogene 60 24317512
2010 Negative regulation of Wnt signaling mediated by CK1-phosphorylated Dishevelled via Ror2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 60 20215527
2020 Targeting Casein Kinase 1 (CK1) in Hematological Cancers. International journal of molecular sciences 59 33261128
2017 CSNK1a1 Regulates PRMT1 to Maintain the Progenitor State in Self-Renewing Somatic Tissue. Developmental cell 58 28943242
2008 PML enhances the regulation of p53 by CK1 in response to DNA damage. Oncogene 55 18246126
2007 Purification of CK1 by affinity chromatography on immobilised axin. Protein expression and purification 54 17434749
1996 Induced release of cell surface protein kinase yields CK1- and CK2-like enzymes in tandem. The Journal of biological chemistry 53 8550544
1999 Optimal sequences for non-phosphate-directed phosphorylation by protein kinase CK1 (casein kinase-1)--a re-evaluation. European journal of biochemistry 50 10095790
2020 CK1α, CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis. Proceedings of the National Academy of Sciences of the United States of America 49 31932442
2018 The FAM83 family of proteins: from pseudo-PLDs to anchors for CK1 isoforms. Biochemical Society transactions 48 29871876
2013 Pyrvinium pamoate does not activate protein kinase CK1, but promotes Akt/PKB down-regulation and GSK3 activation. The Biochemical journal 46 23438105
2008 CKIalpha is associated with and phosphorylates star-PAP and is also required for expression of select star-PAP target messenger RNAs. The Journal of biological chemistry 46 18305108
2016 CK1 in Developmental Signaling: Hedgehog and Wnt. Current topics in developmental biology 45 28236970
2020 RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer. The EMBO journal 43 32965059
2015 Phosphorylation of FADD by the kinase CK1α promotes KRASG12D-induced lung cancer. Science signaling 43 25628462
2002 Biochemical and cellular characteristics of the four splice variants of protein kinase CK1alpha from zebrafish (Danio rerio). Journal of cellular biochemistry 43 12210746
2018 CK1α and IRF4 are essential and independent effectors of immunomodulatory drugs in primary effusion lymphoma. Blood 42 29954751
2017 Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors. Science signaling 42 28655862
2014 The RNA helicase FRH is an ATP-dependent regulator of CK1a in the circadian clock of Neurospora crassa. Nature communications 42 24710172
2005 A second protein kinase CK1-mediated step negatively regulates Wnt signalling by disrupting the lymphocyte enhancer factor-1/beta-catenin complex. Cellular and molecular life sciences : CMLS 42 15747065
2023 PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period. Molecular cell 41 37207626
2007 Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2. The EMBO journal 41 17962809
2023 Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells. Cancer cell 39 36898380
2019 Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome. Leukemia 39 30651631
2016 The nucleolar protein NIFK promotes cancer progression via CK1α/β-catenin in metastasis and Ki-67-dependent cell proliferation. eLife 39 26984280
2013 CK1 is required for a mitotic checkpoint that delays cytokinesis. Current biology : CB 38 24055157
2005 Protein kinase CK1alpha regulates mRNA binding by heterogeneous nuclear ribonucleoprotein C in response to physiologic levels of hydrogen peroxide. The Journal of biological chemistry 38 15687492
2022 Decoupling PER phosphorylation, stability and rhythmic expression from circadian clock function by abolishing PER-CK1 interaction. Nature communications 37 35810166
2019 FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning. EMBO reports 37 31338967
2014 Hedgehog-induced phosphorylation by CK1 sustains the activity of Ci/Gli activator. Proceedings of the National Academy of Sciences of the United States of America 37 25512501
2007 Chemical dissection of the APC Repeat 3 multistep phosphorylation by the concerted action of protein kinases CK1 and GSK3. Biochemistry 37 17910481
2024 Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines. Nature communications 36 38228616
2019 Small molecule modulators targeting protein kinase CK1 and CK2. European journal of medicinal chemistry 36 31400711
2017 Role of protein kinases CK1α and CK2 in multiple myeloma: regulation of pivotal survival and stress-managing pathways. Journal of hematology & oncology 36 28969692
2008 Identification of novel protein kinase CK1 delta (CK1delta) inhibitors through structure-based virtual screening. Bioorganic & medicinal chemistry letters 36 18799313
2006 The first armadillo repeat is involved in the recognition and regulation of beta-catenin phosphorylation by protein kinase CK1. Proceedings of the National Academy of Sciences of the United States of America 35 17172446
2013 Control of epithelial cell migration and invasion by the IKKβ- and CK1α-mediated degradation of RAPGEF2. Developmental cell 34 24290981
2012 Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo. PloS one 34 22235331
2012 Aspergillus nidulans CkiA is an essential casein kinase I required for delivery of amino acid transporters to the plasma membrane. Molecular microbiology 34 22489878
2009 Differential phosphorylation of occludin and tricellulin by CK2 and CK1. Annals of the New York Academy of Sciences 34 19538290
1994 Cloning and chromosomal localization of the gene coding for human protein kinase CK1. FEBS letters 34 8050587
2017 Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and β-catenin survival signaling pathways. Oncotarget 33 28099937
2017 CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation. Proceedings of the National Academy of Sciences of the United States of America 33 28878021
2009 Regulation of dynein-driven microtubule sliding by the axonemal protein kinase CK1 in Chlamydomonas flagella. The Journal of cell biology 33 19752022
2009 Isoform specific phosphorylation of p53 by protein kinase CK1. Cellular and molecular life sciences : CMLS 33 20041275
2009 Autophosphorylation of carboxy-terminal residues inhibits the activity of protein kinase CK1alpha. Journal of cellular biochemistry 30 19115251
2022 S100A16 promotes acute kidney injury by activating HRD1-induced ubiquitination and degradation of GSK3β and CK1α. Cellular and molecular life sciences : CMLS 28 35279748
2013 Systems biology approach identifies the kinase Csnk1a1 as a regulator of the DNA damage response in embryonic stem cells. Science signaling 28 23354688
2007 Posttranslational regulation of Neurospora circadian clock by CK1a-dependent phosphorylation. Cold Spring Harbor symposia on quantitative biology 28 18419275
2005 Generation of protein kinase Ck1alpha mutants which discriminate between canonical and non-canonical substrates. The Biochemical journal 28 15975091
2022 Kinase domain autophosphorylation rewires the activity and substrate specificity of CK1 enzymes. Molecular cell 26 35353987
2014 The tumor suppressor APC differentially regulates multiple β-catenins through the function of axin and CKIα during C. elegans asymmetric stem cell divisions. Journal of cell science 26 24762815
2005 Characterization of two T. gondii CK1 isoforms. Molecular and biochemical parasitology 26 15811523
2000 Human CKIalpha(L) and CKIalpha(S) are encoded by both 2.4- and 4. 2-kb transcripts, the longer containing multiple RNA-destablising elements. Biochimica et biophysica acta 26 11004513
2019 Prosurvival autophagy is regulated by protein kinase CK1 alpha in multiple myeloma. Cell death discovery 25 31123604
2018 A CK1 FRET biosensor reveals that DDX3X is an essential activator of CK1ε. Journal of cell science 25 29222110
2018 CK1/Doubletime activity delays transcription activation in the circadian clock. eLife 25 29611807
2018 CK1α Collaborates with DOUBLETIME to Regulate PERIOD Function in the Drosophila Circadian Clock. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 30373768
2018 A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 25 30487124
2017 Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis. Oncogene 25 28945225
2008 Phosphorylation of RhoB by CK1 impedes actin stress fiber organization and epidermal growth factor receptor stabilization. Experimental cell research 24 18590726
2021 Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2. International journal of molecular sciences 23 33918307
2021 CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1. The Journal of cell biology 22 34726688
1996 The recombinant alpha isoform of protein kinase CK1 from Xenopus laevis can phosphorylate tyrosine in synthetic substrates. European journal of biochemistry 22 9022677
2008 A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro. Biological & pharmaceutical bulletin 21 18239272
2021 FRQ-CK1 Interaction Underlies Temperature Compensation of the Neurospora Circadian Clock. mBio 20 34182774
2012 Exploiting the MDM2-CK1α protein-protein interface to develop novel biologics that induce UBL-kinase-modification and inhibit cell growth. PloS one 20 22916255
2003 CK1 and GSK3 in the Drosophila and mammalian circadian clock. Novartis Foundation symposium 20 14712927
2020 FAM83F regulates canonical Wnt signalling through an interaction with CK1α. Life science alliance 18 33361109
2023 Design and Development of IKZF2 and CK1α Dual Degraders. Journal of medicinal chemistry 17 38085607
2015 CSNK1A1 mutations and isolated del(5q) abnormality in myelodysplastic syndrome: a retrospective mutational analysis. The Lancet. Haematology 17 26688096

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